The present invention relates to novel nitrogen-containing condensed cyclic compounds (preferably quinazoline derivatives) which have a superior anti-allergic action, anti-histaminic action, anti-inflammatory action, eosinophil chemotaxis-inhibiting action and so on, and are useful as agents for preventing or treating allergic diseases, atopic dermatitis, allergic rhinitis, asthma (e.g., bronchial asthma), allergic conjunctivitis, urticaria (e.g., chronic urticaria), etc., a method for producing them, a composition and so on.
In these days, compounds having a nitrogen-containing condensed ring (e.g., quinazoline) backbone as a drug against various diseases have been extensively synthesized, including:
(1) a compound disclosed in JP-A-57-206665 represented by the formula: 
[wherein each of R1 and R3 is a lower alkyl group, R2 is a straight or branched alkoxycarbonyl group, R1, R2 and R3 are bound to 5-, 6- and 7-positions, or 6-, 7- and 8-position in a quinazoline ring, R4 is a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group or a nitro group, X is an alkylene group optionally having an alkyl side chain, Y is a nitrogen atom or a CH moiety, each of R5, R6 and R7 is a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, each of R8 and R9 is a hydrogen atom or a lower alkyl group, m is an integer of 0 to 3 and n is 0 or 1], or a salt thereof which is purported to be useful as a vasodilator, a blood flow-improving agent, a hypotensive agent or an anti-arteriosclerotic agent;
(2) a compound disclosed in JP-A-60-152417 represented by the formula: 
[wherein R is a hydrogen atom or a fluorine atom] or a salt thereof which is purported to be useful as an anti-cancer effect-promoting agent;
(3) a compound disclosed in EP-A-040793 represented by the formula: 
[wherein each of R1 and R3 is an alkyl group, R2 is an alkoxycarbonyl group, B is an alkyl group or a phenyl group optionally substituted with at least one halogen, alkyl, alkoxy, dialkylamino, Oxe2x80x94CH2xe2x80x94O, CF3 or NO2, A is a hydrogen atom, an alkyl group, a carboxy-alkyl group, an alkoxycarbonyl-alkyl group, a hydroxyalkyl group, a benzyl group optionally substituted with NO2 or a lower alkoxy, an aminoalkyl group substituted with pentamethylene, hexamethylene, heptamethylene, methylene optionally substituted with pyridylmethyl, alkyl, alkoxy, benzyl, tetramethylene, alkyl, a lower alkyl group substituted with piperidine or pyrrolidine, R4R5Nxe2x80x94COxe2x80x94X, R6R7Nxe2x80x94X1xe2x80x94Oxe2x80x94COxe2x80x94X, a group represented by the formula: 
[wherein each of X and X1 is a lower alkylene group, R4 is a hydrogen atom or an alkyl group, R5 is a hydrogen atom, an alkyl group, a dialkylamino-alkyl group, a benzyl group, piperidino-morpholino, 1-piperazinyl, a 4-(lower)acyl-1-piperazinyl, a 4-carbamoyl-1-piperazinyl-alkyl group whose carbamoyl group is optionally substituted with alkyl or phenyl, or NR4R5 is piperidino or 4-alkylpiperazino, R6 is an alkyl group, R7 is an alkyl group, a benzyl group, a piperidino group-alkyl, morpholino-alkyl], or a salt thereof which is purported to be useful as an anti-arteriosclerotic agent;
(4) a compound disclosed in U.S. Pat. No. 3,274,194. represented by the formula: 
[wherein R1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group or an amino group, n is an integer of 0 to 6, R2 is a di-lower alkylamino or a heterocyclic group], or a salt thereof which is purported to be useful as an anti-inflammatory agent or a sedative; or,
(5) a compound disclosed in JP-A-1-213284 represented by the formula: 
[wherein one of X, Y and Z is a sulfur atom, and the others are carbon atoms, E and G are same or different and each is an oxygen atom or a sulfur atom, R1 is a substituted piperidino group or a substituted 1-piperazinyl group (substituent is an aralkyl group, an aralkyloxy group, an aralkylcarbonyl group, an aromatic acyl group or an aralkylidene group), R2 and R3 are same or different and each is a hydrogen atom, a lower alkyl group, an aryl group or a halogen atom, R4 is a hydrogen atom, a lower alkyl group or an acyl group, A is an alkylene group having 1 to 4 carbon atoms], or a salt thereof which is purported to have an anti-histaminic action, an anti-serotonin action, an anti-allergic action and an anti-asthmatic action.
On the other hand, examples of a compound having an anti-allergic action or an anti-histaminic action are Terfenadine (The Merck Index, 12th ed., 9307) and Ebastine (The Merck Index, 12th ed., 3534), which are used clinically.
A novel compound which is more satisfactory in terms of efficacy, duration of action, safety and the like when compared with conventional anti-allergic agents, anti-histaminic agents, anti-inflammatory agents and the like is still desired.
The inventors of this invention made an effort and finally synthesized for the first time a novel nitrogen-containing condensed ring compound (preferably a quinazoline derivative) represented by the formula: 
[wherein ring A represents a cyclic hydrocarbon optionally having substituents or a nitrogen-containing heterocycle optionally having substituents; D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom; one of R1 and R2represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent, independently, an aromatic group optionally having substituents; Ar1 and Ar2 may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom; ring B represents a nitrogen-containing heterocycle optionally having substituents; X and Y are the same or different and represent, independently, a bond, an oxygen atom, S(O)p (p represents an integer of 0 to 2), NR4 (R4 represents a hydrogen atom or a lower alkyl group) or a bivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituents; and R3 represents ahydrogen atom, a hydroxy group optionally having substituents or an optionally esterified carboxyl group); and the other is a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents], or its salt whose chemical structure is characterized substantially in that two substituents bound to one of two nitrogen atoms of the nitrogen-containing condensed ring (preferably a quinazoline) backbone via a spacer having a nitrogen-containing heterocycle such as piperidine or piperazine, and discovered that this compound has unexpectedly excellent anti-allergic action, anti-histaminic action, anti-inflammatory action, eosinophil chemotaxis-inhibiting action (especially as a combination of an anti-histaminic action with an eosinophil chemotaxis-inhibiting action) and excellent duration of the action and safety and undergoes an extremely low migration into the brain, based on which it is considered to be useful as a prophylactic and therapeutic agent against atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria and the like, thereby establishing the present invention.
That is, the present invention relates to:
[1] A compound represented by the formula: 
[wherein ring A represents a cyclic hydrocarbon optionally having substituents or a nitrogen-containing heterocycle optionally having substituents; D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom; one of R1 and R2 represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent, independently, an aromatic group optionally having substituents; Ar1 and Ar2 may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom; ring B represents a nitrogen-containing heterocycle optionally having substituents; X and Y are the same or different and represent, independently, a bond, an oxygen atom, S(O)p (p represents an integer of 0 to 2), NR4 (R4 represents a hydrogen atom or a lower alkyl group) or a bivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituents; and R3 represents a hydrogen atom, a hydroxy group optionally having substituents or an optionally esterified carboxyl group); and the other is a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents], or a salt thereof,
[2] A compound as defined in [1], wherein ring A represents (1) a 3- to 10-membered cyclic hydrocarbon or (2) a 3- to 13-membered nitrogen-containing heterocycle which contains one nitrogen atom and may further contain 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino and, 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) a di-C1-6 alkylcarbamoyl group,
(V) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-6 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) a C6-10 aryl-carbamoyl group,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(xxvi) a C7-15 aralkyl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(X) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(xxvii) a C6-10 aryloxy group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(xxviii) a C7-16 aralkyloxy group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(xxix) an oxo group,
(xxx) a thiocarbamoyl group,
(xxxi) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxii) a di-C1-6 alkyl-thiocarbamoyl group,
(xxxiii) a C6-10 aryl-thiocarbamoyl group,
(xxxiv) C6-10 aryl-carbonyloxy,
(xxxv) aminocarbonyl optionally having
(a) a halogen atom,
(b) optionally halogenated C1-6 alkyl,
(c) optionally halogenated C2-6 alkenyl,
(d) optionally halogenated C2-6 alkynyl,
(e) C3-6 cycloalkyl,
(f) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(g) optionally halogenated C1-6 alkylthio,
(h) hydroxy,
(i) amino,
(j) mono-C1-6 alkylamino,
(k) di-C1-6 alkylamino,
(l) 5- to 6-membered cyclic amino,
(m) C1-6alkyl-carbonyl,
(n) carboxyl,
(o) C1-6 alkoxy-carbonyl,
(p) carbamoyl,
(q) mono-C1-6 alkyl-carbamoyl,
(r) di-C1-6 alkylcarbamoyl,
(s) C6-10 aryl-carbamoyl,
(t) sulfo,
(u) C1-6 alkylsulfonyl,
(v) C6-10 aryl,
(w) C6-10 aryloxy,
(x) C7-16 aralkyloxy,
(y) thiocarbamoyl,
(z) mono-C1-6 alkyl-thiocarbamoyl,
(aa) di-C1-6 alkyl-thiocarbamoyl,
(bb) C6-10 aryl-thiocarbamoyl,
(cc) C7-16 aralkyl,
(dd) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ee) a carboxyl-C1-6 alkyl group,
(xxxvi) a 5- or 6-membered heterocyclic group which contains one or two kinds of and 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom,
(xxxvii) a C1-6 alkoxy-carbonyl-C1-6 alkoxy-carbonyl group,
(xxxviii) a C1-6 alkykoxy-carbonyl-C1-6 alkyl-carbamoyl group,
(xxxix) a hydroxy-C1-6 alkyl-carbamoyl group,
(xxxx) a C1-6 alkoxy-carbonyl-carbamoyl group,
(xxxxi) C6-14 arylsulfonamide,
(xxxxii) C1-6 alkylsulfonamide,
(xxxxiii) a carboxy-C1-6 alkyl-carbonyl-amino group,
(xxxxiv) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl-amino group,
(xxxxv) a C1-6 alkyl-carbonyloxy-C1-6 alkyl-carbonyl-amino group,
(xxxxvi) a hydroxy-C1-6 alkyl-carbonyl-amino group, and
(xxxxvii) a C6-14 aryl-C2-6 alkenyl-carbonylamido group which may be substituted by hydroxy or/and C1-6 alkoxy;
D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom;
one of R1 and R2represents a group represented by the formula: 
wherein R3 represents
(1) a hydrogen atom,
(2) a hydroxy group which may have a C1-16 chained or cyclic hydrocarbon group optionally having substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) C6-10 aryl-carbamoyl,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group,
(xxvi) a C6-10 aryloxy group,
(xxvii) a C7-16 aralkyloxy group,
(xxviii) an oxo group,
(xxix) a thiocarbamoyl group,
(xxx) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxi) a di-C1-6 alkyl-thiocarbamoyl group and
(xxxii) C6-10 aryl-thiocarbamoyl and
(xxxiii) a C7-16 aralkyl group,
(3) a carboxyl group, or
(4) a carboxyl group which may have a C1-16 chained or cyclic hydrocarbon group optionally having substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) C6-10 aryl-carbamoyl,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group,
(xxvi) a C6-10 aryloxy group,
(xxvii) a C7-16 aralkyloxy group,
(xxviii) an oxo group,
(xxix) a thiocarbamoyl group,
(xxx) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxi) a di-C1-6 alkyl-thiocarbamoyl group and
(xxxii) C6-10 aryl-thiocarbamoyl and
(xxxiii) a C7-16 aralkyl group, instead of a hydrogen atom of the carboxyl group;
Ar1 and Ar2 represent, independently,
(1) a C6-14 aryl group, (2) a 5- to 8-membered aromatic heterocyclic group which contains one or two kinds of and 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom or (3) a condensed heterocyclic group of the 5- to 8-membered aromatic heterocyclic group and a C6 14 aromatic cyclic hydrocarbon, which may have substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) C6-10 aryl-carbamoyl,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group,
(xxvi) a C6-10 aryloxy group,
(xxvii) a C7-6 aralkyloxy group,
(xxviii) an oxo group,
(xxix) a thiocarbamoyl group,
(xxx) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxi) a di-C1-6 alkyl-thiocarbamoyl group and
(xxxii) C6-10 aryl-thiocarbamoyl and
(xxxiii) a C7-16 aralkyl group;
Ar1 and Ar2 may form a condensed cyclic group represented by the formula: 
[wherein R3 represents the same meaning as defined above], optionally having the same substituents as the substituents for the aromatic group represented by the above-mentioned Ar1 and Ar2, together with an adjacent carbon atom; ring B represents a 3- to 13-membered nitrogen-containing heterocycle which contains one nitrogen atom and may further have 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) C6-10 aryl-carbamoyl,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group,
(xxvi) a C6-10 aryloxy group,
(xxvii) a C7-16 aralkyloxy group,
(xxviii) an oxo group,
(xxix) a thiocarbamoyl group,
(xxx) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxi) a di-C1-6 alkyl-thiocarbamoyl group and
(xxxii) C6-10 aryl-thiocarbamoyl and
(xxxiii) a C7-16 aralkyl group;
X and Y is the same or different and represent, (1) a bond, (2) an oxygen atom, (3) S(O)p (p represents an integer of 0 to 2), (4) NR4 (R4 represents a hydrogen atom or a C1-6 alkyl group), or
(5) a C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group which may contain 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the hydrocarbon chain, which may have substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) C6-10 aryl-carbamoyl,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group,
(xxvi) a C6-10 aryloxy group,
(xxvii) a C7-16 aralkyloxy group,
(xxviii) an oxo group,
(xxix) a thiocarbamoyl group,
(xxx) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxi) a di-C1-6 alkyl-thiocarbamoyl group, and
(xxxii) C6-10 aryl-thiocarbamoyl and
(xxxiii) a C7-16 aralkyl group; and the other is (1) a hydrogen atom, (2) a cyano group, or (3) a C-1-16 chained or cyclic hydrocarbon group which may have substituents selected from the group consisting of
(i) a halogen atom,
(ii) a C1-3 alkylenedioxy group,
(iii) a nitro group,
(iv) a cyano group,
(v) a C1-6 alkyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5 to 10 membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vi) C2-6 alkenyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(vii) C2-6 alkynyl group optionally having substituents selected from the group consisting of a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(viii) a C3-6 cycloalkyl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) a di-C1-6 alkylcarbamoyl group,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(X) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl.
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) a carboxyl-C1-6 alkyl group,
(ix) a C1-6 alkoxy group optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(x) an optionally halogenated C1-6 alkylthio group,
(xi) a hydroxy group,
(xii) an amino group,
(xiii) a mono-C1-6 alkylamino group,
(xiv) a di-C1-6 alkylamino group,
(xv) a 5- to 6-membered cyclic amino group,
(xvi) a C1-6 alkyl-carbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkoxy-carbonyl group,
(xix) a carbamoyl group,
(xx) a mono-C1-6 alkyl-carbamoyl group,
(xxi) a di-C1-6 alkylcarbamoyl group,
(xxii) a C6-10 aryl-carbamoyl group,
(xxiii) a sulfo group,
(xxiv) a C1-6 alkylsulfonyl group,
(xxv) a C6-10 aryl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) carboxyl-C1-6 alkyl,
(xxvi) a C7-15 aralkyl group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) carboxyl-C1-6 alkyl,
(xxvii) a C6-10 aryloxy group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl, or
(ii) carboxyl-C1-6 alkyl,
(xxviii) a C7-16 aralkyloxy group which may be substituted by
(a) a halogen atom,
(b) C1-3 alkylenedioxy,
(c) nitro,
(d) cyano,
(e) optionally halogenated C1-6 alkyl,
(f) optionally halogenated C2-6 alkenyl,
(g) optionally halogenated C2-6 alkynyl,
(h) C3-6 cycloalkyl,
(i) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono-or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(j) optionally halogenated C1-6 alkylthio,
(k) hydroxy,
(l) amino,
(m) mono-C1-6 alkylamino,
(n) di-C1-6 alkylamino,
(o) 5- to 6-membered cyclic amino,
(p) C1-6 alkyl-carbonyl,
(q) carboxyl,
(r) C1-6 alkoxy-carbonyl,
(s) carbamoyl,
(t) mono-C1-6 alkyl-carbamoyl,
(u) di-C1-6 alkylcarbamoyl,
(v) C6-10 aryl-carbamoyl,
(w) sulfo,
(x) C1-6 alkylsulfonyl,
(y) C6-10 aryl,
(z) C6-10 aryloxy,
(aa) C7-16 aralkyloxy,
(bb) oxo,
(cc) thiocarbamoyl,
(dd) mono-C1-6 alkyl-thiocarbamoyl,
(ee) di-C1-6 alkyl-thiocarbamoyl,
(ff) C6-10 aryl-thiocarbamoyl,
(gg) C7-16 aralkyl,
(hh) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ii) carboxyl-C1-6 alkyl,
(xxix) an oxo group,
(xxx) a thiocarbamoyl group,
(xxxi) a mono-C1-6 alkyl-thiocarbamoyl group,
(xxxii) a di-C1-6 alkyl-thiocarbamoyl group,
(xxxiii) a C6-10 aryl-thiocarbamoyl group,
(xxxiv) C6-10 aryl-carbonyloxy,
(xxxv) aminocarbonyl optionally having
(a) a halogen atom,
(b) optionally halogenated C1-6 alkyl,
(c) optionally halogenated C2-6 alkenyl,
(d) optionally halogenated C2-6 alkynyl,
(e) C3-6 cycloalkyl,
(f) C1-6 alkoxy optionally having substituents selected from a halogen atom, hydroxy, carboxyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di-C1-6 alkylamino, mono- or di-C1-6 alkyl-carbonylamino, sulfonamido, C1-6 alkyl-sulfonamido optionally having mono- or di-C1-6 alkylamino, and 5- to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof,
(g) optionally halogenated C1-6 alkylthio,
(h) hydroxy,
(i) amino,
(j) mono-C1-6 alkylamino,
(k) di-C1-6 alkylamino,
(l) 5- to 6-membered cyclic amino,
(m) C1-6 alkyl-carbonyl,
(n) carboxyl,
(o) C1-6 alkoxy-carbonyl,
(p) carbamoyl,
(q) mono-C1-6 alkyl-carbamoyl,
(r) a di-C1-6 alkylcarbamoyl,
(s) C6-10 aryl-carbamoyl,
(t) sulfo,
(u) C1-6 alkylsulfonyl,
(v) C6-10 aryl,
(w) C6-10 aryloxy,
(x) C7-16 aralkyloxy,
(y) thiocarbamoyl,
(z) mono-C1-6 alkyl-thiocarbamoyl,
(aa) di-C1-6 alkyl-thiocarbamoyl,
(bb) C6-10 aryl-thiocarbamoyl,
(cc) C7-16 aralkyl,
(dd) C1-6 alkoxy-carbonyl-C1-6 alkyl or
(ee) a carboxyl-C1-6 alkyl group,
(xxxvi) a 5- or 6-membered heterocyclic group which contains one or two kinds of and 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom,
(xxxvii) a C1-6 alkoxy-carbonyl-C1-6 alkoxy-carbonyl group,
(xxxviii) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbamoyl group,
(xxxix) a hydroxy-C1-6 alkyl-carbamoyl group,
(xxxx) a C1-6 alkoxy-carbonyl-carbamoyl group,
(xxxxi) C6-14 arylsulfonamide,
(xxxxii) C1-6 alkylsulfonamide,
(xxxxiii) carboxy-C1-6 alkyl-carbonyl-amino group,
(xxxxiv) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl-amino group,
(xxxxv) a C1-6 alkyl-carbonyloxy-C1-6 alkyl-carbonyl-amino group,
(xxxxvi) a hydroxy-C1-6 alkyl-carbonyl-amino group, and
(xxxxvii) a C6-14 aryl-C2-6 alkenyl-carbonylamido group which may be substituted by hydroxy or/and C1-6 alkoxy,
[3] A compound as defined in [1] wherein ring A is a benzene ring optionally having substituents, a pyridine ring optionally having substituents or a pyrazine ring optionally having substituents,
[4] A compound as defined in [1] wherein Ar1 and Ar2 are independently a phenyl group optionally having substituents,
[5] A compound as defined in [1] wherein X is a bond or C1-6 alkylene group,
[6] A compound as defined in [1] wherein Y is a bond, an oxygen atom or a C1-6 alkylene group, which may contain an oxygen atom in the alkylene chain, optionally substituted by a hydroxy group,
[7] A compound as defined in [1] wherein ring B is a ring represented by the formula: 
[wherein Z represents a nitrogen atom or a methyne group, Z1 and Z2 are the same or different and represent, independently, a straight chained C1-6 alkylene group optionally substituted by a hydroxy group, an oxo group or a C1-6 alkyl group],
[8] A compound as defined in [1] wherein ring B is 
[9] A compound as defined in [1] wherein R3 is a hydrogen atom or a hydroxy group,
[10] A compound as defined in [1] wherein one of R1 and R2 is a group represented by the formula: 
(wherein each symbol represents the same meaning as defined in [1], and the other is a hydrogen atom, a cyano group, an optionally substituted C1-6 alkyl group or an optionally substituted C3-6 cycloalkyl group,
[11] A compound as defined in [1] wherein both D and E are an oxygen atom,
[12] A compound as defined in [1] wherein ring A is a C6-14 aryl ring optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a nitro group, (iii) a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl, (iv) a C1-6 alkoxy group, (v) a hydroxy group, (vi) an amino group, (vii) a mono- or di-C1-6 alkylamino group, (viii) a carboxyl group, (ix) a C1-6 alkoxy-carbonyl group, (x) a 5- to 6-membered heterocyclic group which contains one or two kinds of and 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, (xi) C1-6 alkylsulfonamide, (xii) a carboxy-C1-6 alkyl-carbonyl-amino group, (xiii) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl-amino group, (xiv) a C1-6 alkyl-carbonyl-oxy-C1-6 alkyl-carbonyl-amino group and (xv) a C6-14 aryl-C2-6 alkenyl-carbonylamido group which may be substituted by hydroxy or/and C1-6 alkoxy; D and E are an oxygen atom; one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X is a C1-6 alkylene group, Y is a bond or an oxygen atom, R3 is a hydrogen atom or a hydroxy group); the other is (1) a hydrogen atom, (2) a cyano group, (3) a C1-16 alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a carboxyl group, (iii) a C1-6 alkoxy-carbonyl group, (iv) a 5- to 6-membered nitrogen-containing heterocyclic group, (v) a carbamoyl group optionally having substituents selected from C7-15 aralkyl, carboxyl-C1-6 alkyl and C1-6 alkoxycarbonyl-C1-6 alkyl, (vi) C6-14 aryl-carbonyloxy group, (vii) a sulfamoyl group, (viii) a mono- or di-C1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) a C1-6 alkoxy group optionally having carboxyl or carbamoyl and (x) cyano, (4) a C3-7 cycloalkyl group optionally having carboxyl or C1-6 alkoxycarbonyl, (5) a C6-14 aryl group, or (6) a C7-15 aralkyl group optionally having substituents selected from C1-6 alkoxy, carboxyl or C1-6 alkoxy-carbonyl,
[13] A compound as defined in [1] wherein ring A is a benzene ring optionally having (i) a halogen atom or (ii) C1-6 alkoxy-carbonyl;
D and E are an oxygen atom;
one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X is a C1-6 alkylene group, Y is an oxygen atom, R3 is a hydrogen atom or a hydroxy group); the other is (1) a hydrogen atom, (2) a cyano group, (3) a C1-6 alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a C1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) cyano, (4) a C3-7 cycloalkyl group optionally having C1-6 alkoxycarbonyl,
[14] A compound as defined in [1] wherein ring A is a benzene ring optionally having a halogen atom;
D and E are an oxygen atom;
one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X is a C1-6 alkylene group, Y is an oxygen atom, R3is a hydrogen atom); the other is a C1-6 alkyl group optionally having carboxyl,
[15] 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-valeric acid or a salt thereof,
[16] 2-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino) butyl]-1,2,3,4-tetrahydroquinazoline-3-yl]isobutyric acid or a salt thereof,
[17] 2-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino) butyl]-6-fluoro-1,2,3,4-tetrahydroquinazoline-3-yl]isobutyric acid or a salt thereof,
[18] A method for producing a compound as defined in (1) which is characterized in reacting a compound represented by the formula: 
[wherein Q1 represents a leaving group and other symbols represent the same meanings as defined in [1]], or a salt thereof with a compound represented by the formula: 
[wherein Q2 represents a reactive group, R2xe2x80x2 represents a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents and other symbols represent the same meanings as defined in [1]], or a salt thereof,
[19] A method for producing a compound as defined in [1] which is characterized in reacting a compound represented by the formula: 
[wherein each symbol represents the same meanings as defined in [1]], or a salt thereof with Q3xe2x80x94COxe2x80x94Q4 (Q3 and Q4 represent independently a leaving group), and subjecting it to a ring-closure reaction,
[20] A pharmaceutical composition which comprises a compound as defined in [1] or a salt thereof,
[21] An anti-histaminic and/or eosinophil chemotaxis-inhibiting agent which comprises a compound as defined in [1] or a salt thereof,
[22] An anti-allergic agent which comprises a compound as defined in [1] or a salt thereof,
[23] An agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, urticaria or atopic dermatitis which comprises a compound as defined in [1] or a salt thereof,
[24] A method for treating asthma, allergic conjunctivitis, allergic rhinitis, urticaria or atopic dermatitis in mammals which comprises administrating to a subject in need an effective amount of a compound as defined in [1], and
[25] Use of a compound as defined in [1] for manufacturing an agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, urticaria or atopic dermatitis.
And, when the compound (I) or a salt thereof has asymmetric carbons in its structure, optically-active forms and racemates are included in a scope of the present invention, and the compound (I) or a salt thereof may be any one of hydrate and non-hydrate.
In the formula (I), one of R1 and R2 represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent, independently, an aromatic group optionally having substituents; Ar1 and Ar2 may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom; ring B represents a nitrogen-containing heterocycle optionally having substituents; X and Y is the same or different and represent, independently, a bond, an oxygen atom, S(O)p (p represents an integer of 0 to 2), NR4 (R4 represents a hydrogen atom or a lower alkyl group) or a bivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituents; and R3 represents ahydrogen atom, a hydroxy group optionally having substituents or an optionally esterified carboxyl group). The other is a hydrogen atom or a hydrocarbon group optionally having substituents.
In the above mentioned formula (II), Ar1 and Ar2 represent xe2x80x9can aromatic group optionally having substituentsxe2x80x9d, and Ar1 and Ar2 may form a condensed cyclic group optionally having substituents together with an adjacent carbon atom.
As the xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by Ar1 and Ar2, for example,
{circle around (1)} monocyclic, condensed polycyclic or gathered cyclic aromatic hydrocarbon group, more specifically a 6- to 14-monocyclic, condensed polycyclic or gathered cyclic aromatic hydrocarbon group such as a C6-14 aryl group such as phenyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl (preferably, phenyl, biphenyl, 1-naphthyl or 2-naphthyl, particularly preferably phenyl, etc.), or
{circle around (2)} monocycle (preferably 5- to 8-membered) or its condensed aromatic heterocyclic group which contains preferably one or two kinds of and not less than one (for example, 1 to 4, preferably 1 to 3) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, more specifically, aromatic heterocycles such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, thianthrene, furan, isoindolylzine, xanthene, phenoxazine, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine or isochroman (preferably, pyridine, thiophene or furan, etc., more preferably pyridine, etc.), or a group formed by removing any one hydrogen atom from the condensed ring formed by these rings (preferably, above-mentioned monocyclic heterocycle) and one or a few (preferably 1 or 2, more preferably 1) aromatic rings (for example, the above-mentioned aromatic hydrocarbon group, etc., preferably benzene ring, etc.), etc. are exemplified.
As the xe2x80x9caromatic ringxe2x80x9d of the xe2x80x9caromatic ring optionally having substituentsxe2x80x9d represented by Ar1 and Ar2, for example, phenyl, etc. are preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic ring optionally having substituentsxe2x80x9d, for example, (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (iii) a nitro group, (iv) a cyano group, (v) an optionally substituted lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (vi) an optionally substituted lower alkenyl group (e.g., a C2-6 alkenyl group such as vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.), (vii) an optionally substituted lower alkynyl group (e.g., a C2-6 alkynyl group such as 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.), (viii) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (ix) an optionally substituted lower alkoxy (e.g., a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (x) an optionally halogenated lower alkylthio group, (xi) a hydroxy group, (xii) an amino group, (xiii) a mono-lower alkylamino group(e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xiv) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (xvi) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (xvii) a carboxyl group, (xviii) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix) a carbamoyl group, (xx) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (xxi) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxii) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiii) a sulfo group, (xxiv) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (xxv) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (xxvi) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (xxvii) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (xxviii) an oxo group, (xxix) a thiocarbamoyl group, (xxx) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxi) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (xxxii) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (xxxiii) an aralkyl group (e.g., a C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (xxxiv) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (xxxv) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc. are exemplified.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d, xe2x80x9coptionally substituted lower alkenyl groupxe2x80x9d, xe2x80x9coptionally substituted lower alkynyl groupxe2x80x9d and xe2x80x9coptionally substituted lower alkoxy groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2, for example, 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (ii) a mono- or di-lower alkylamino group (e.g., a mono- or di-C1-6 alkylamino group such as methylamino, dimethylamino, ethylamino, dimethylamino, etc.), (iii) a lower alkoxy-carbonyl group (e.g., a C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, etc.), (iv) an aminocarbonyl group, (v) a carboxyl group and (vi) 5-to 10-membered heterocyclic group which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom or a benzo-condensed cyclic group thereof, are exemplified. Of the above-mentioned substituents, as the lower alkyl group optionally substituted by a halogen atom (optionally halogenated lower alkyl group), for example, a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.), etc. are used. As the lower alkenyl group optionally substituted by a halogen atom (optionally halogenated lower alkenyl) and the lower alkynyl group optionally substituted by a halogen atom (optionally halogenated lower alkynyl), a C2-6 alkenyl group (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) and a C2-6 alkynyl group (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) which may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) are used.
As the xe2x80x9coptionally halogenated lower alkylthio groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2, for example, a lower alkylthio group (e.g., a C1-6 alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), etc. are exemplified, and as specific examples, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. are exemplified.
1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2 may substitute at the position on the aromatic group where substitution is possible.
And, when the xe2x80x9caromatic groupxe2x80x9d has not less than two substitutents, each substituent may be same or different.
As specific examples of the xe2x80x9ccondensed cyclic groupxe2x80x9d when Ar1 and Ar2 form a condensed cyclic group optionally having substituents together with an adjacent carbon atom for example, condensed cyclic groups represented by the formulae: 
(wherein R3 represents the same meaning as defined above), etc. are exemplified.
As the substituents for these condensed cyclic group, for example, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2xe2x80x3, etc. are exemplified, and these condensed cyclic group may have same or different 1 to 5, preferably 1 to 3, more preferably 1 or 2 substituents at the position on the condensed ring where substitution is possible.
As Ar1 and Ar2, a monocyclic or condensed polycyclic aromatic hydrocarbon group is similarly or differently preferred, and a phenyl group optionally having substituents is more preferred, and an unsubstituted phenyl group is further more preferred.
In the above mentioned formula (II), ring B represents a xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d.
As the xe2x80x9cnitrogen-containing heterocyclexe2x80x9d of the xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d represented by ring B, for example, a 3- to 13-membered nitrogen-containing heterocycle which contains one nitrogen atom and may contain further 1 to 3 (preferably 1 or 2, more preferably 1) hetero atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and so on, etc. are exemplified, and particularly those which bind to X of the above-mentioned formula (II) through the nitrogen atom of the nitrogen-containing heterocycle are preferred.
As preferable specific examples of ring B, for example, a ring represented by the formula: 
[wherein Z represents a nitrogen atom or a methyne group, Z1 and Z2 are the same or different and represent, independently, a straight chained C1-6 alkylene group optionally substituted by a hydroxy, oxo or C1-6 alkyl (preferably a sum of carbons of the straight chained C1-6 alkylene group represented by Z1 and Z2 is not less than 2 and not more than 11).], etc. are exemplified. (In specific examples for the ring B, they are described as a bivalent group in order to define a binding position of ring B and X and Y in the above-mentioned formula (II).)
As the xe2x80x9cstraight chained C1-6 alkylene groupxe2x80x9d represented by Z1 and Z2 for example, a straight chained C1-6 alkylene group such as methylene, ethylene, propylene, butylene, etc. is used.
As the xe2x80x9cC1-6 alkylxe2x80x9d represented as the substituent for the xe2x80x9cstraight chained C1-6 alkylene groupxe2x80x9d represented by Z1 and Z2, for example, a straight chained or branched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are exemplified.
As preferable xe2x80x9cstraight chained C1-6 alkylene group optionally substituted by a hydroxy group, an oxo group or a C1-6 alkyl groupxe2x80x9d, an unsubstituted straight chained C1-6 alkylene group, etc. are exemplified.
As ring B, more preferably, piperidine, piperazine, etc. are exemplified. Specifically, for example, a 3- to 9-membered (more preferably 3- to 6-membered) nitrogen -containing heterocycle such as, 
etc. are preferred (In specific examples for the ring B, they are described as a bivalent group in order to define a binding position of ring B and X and Y in the above-mentioned formula (II)). Particularly, those which bind to X of the above-mentioned formula (II) through the nitrogen atom of the nitrogen-containing heterocycle are preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d represented by ring B, for example, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2xe2x80x3 are used, and same or different 1 to 3, preferably 1 or 2, more preferably 1 substituent(s) may substitute at the position on the nitrogen-containing heterocycle where substitution is possible.
In the above-mentioned formula (II), X and Y are the same or different and represent, independently, {circle around (1)} a bond, {circle around (2)} an oxygen atom, {circle around (3)} S(O)p (p represents an integer of 0 to 2), {circle around (4)} NR4 (R4 represents a hydrogen atom or a lower alkyl group) or {circle around (5)} a bivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituents.
As the lower alkyl group represented by R4, a straight chained or branched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are exemplified.
The xe2x80x9cbivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atomxe2x80x9d of the xe2x80x9cbivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituentsxe2x80x9d represented by X and Y, represents, for example, a group which is formed by removing each one hydrogen atom (sum two), which binds to same or different carbon atom, from a lower (C1-6) hydrocarbon, and which may contain hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc. in the hydrocarbon chain.
As the xe2x80x9cbivalent straight-chained lower hydrocarbon groupxe2x80x9d, specifically,
(i) C1-6 alkylene group (e.g., xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94 and xe2x80x94(CH2)6xe2x80x94, etc.),
(ii) C2-6 alkenylene group (e.g., xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, etc.),
(iii) C2-6 alkynylene (e.g., xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, etc.), etc. are exemplified.
As the xe2x80x9csubstituents"" of the xe2x80x9cbivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituentsxe2x80x9d represented by X and Y, for example, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2 are used, and particularly a hydroxy group or an oxo group, etc. are preferred.
As specific examples in case that the xe2x80x9cbivalent straight-chained lower hydrocarbon groupxe2x80x9d of the xe2x80x9cbivalent straight-chained lower hydrocarbon group, which may contain 1 to 3 hetero atoms, optionally having substituentsxe2x80x9d represented by X and Y contains hetero atoms in the hydrocarbon chain, for example, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94, xe2x80x94(CH2)6xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94, xe2x80x94(CH2)3xe2x80x94NHxe2x80x94, xe2x80x94(CH2)4xe2x80x94NHxe2x80x94, xe2x80x94(CH2)3xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)6xe2x80x94NHxe2x80x94, xe2x80x94(CH2)6xe2x80x94Sxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Sxe2x80x94, etc. are exemplified.
As X, a bond or a C1-6 alkylene group, etc. are preferred, particularly a bond, etc. are preferred.
As Y, a bond, an oxygen atom or a C1-6 alkylne group which may contain an oxygen atom in the alkylene chain and may be substituted by a hydroxy group, etc. are preferred, particularly a bond, an oxygen atom, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94or xe2x80x94CH(OH)xe2x80x94, etc. are preferred.
In the above-mentioned formula (II), R3 represents a hydrogen atom, a hydroxy group optionally having substituents or an optionally esterified carboxyl group.
The xe2x80x9chydroxy group optionally having substituentsxe2x80x9d represents, for example, (1) a hydroxy group or (2) a hydroxy group having one xe2x80x9ca hydrocarbon group optionally having substituentsxe2x80x9d, etc. instead of a hydrogen atom of the hydroxy group.
The xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the xe2x80x9chydroxy group having one hydrocarbon group optionally having substituents, etc.xe2x80x9d represent, for example, a group removed one hydrogen atom from a hydrocarbon compound, and as their examples, for example, a straight chained or cyclic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, an cycloalkyl group, an aryl group, an aralkyl group, etc. are exemplified.
Among them, C1-16 chained (straight chained or branched) or cyclic hydrocarbon group, etc. are preferred, and specifically,
(a) alkyl group [preferably, a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)],
(b) an alkenyl group [preferably, a lower alkenyl group (e.g., C2-6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.)],
(c) an alkynyl group [preferably, a lower alkynyl group (e.g., C2-6 alkynyl such as propargyl, ethynyl, butynyl, 1-hexynyl, etc.),
(d) a cycloalkyl group [preferably, a lower cycloalkyl group (e.g., C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl which may condense with a benzene ring optionally having 1 to 3 lower alkoxy groups (e.g., a C1-6 alkoxy group such as methoxy))],
(e) an aryl group (e.g., C6-14 aryl group such as phenyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, etc., preferably a phenyl group),
(f) an aralkyl group [preferably, a lower aralkyl group (e.g., C7-16 aralkyl group such as benzyl, phenetyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc, more preferably a benzyl group)], etc. are exemplified.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the xe2x80x9chydroxy group having one hydrocarbon group optionally having substituents, etc.xe2x80x9d, for example, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2, etc. are used.
The xe2x80x9coptionally esterified carboxyl groupxe2x80x9d represented by R3 represents, for example, (1) a carboxyl group or (2) a carboxyl group having, for example, one xe2x80x9ca hydrocarbon group optionally having substituentsxe2x80x9d, etc. instead of a hydrogen atom of the carboxyl group.
As the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the xe2x80x9ccarboxyl group having one of hydrocarbon group optionally having substituents, etc.xe2x80x9d, for example, the same those as the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d of the xe2x80x9chydroxy group having one hydrocarbon group optionally having substituents, etc.xe2x80x9d, etc. are exemplified.
As R3, a hydrogen atom, a hydroxy group or a carboxyl group, etc. are preferred, and a hydrogen atom or a hydroxy group, etc. are more preferred, and particularly a hydrogen atom, etc. are preferred.
In the above-mentioned formula (I), one of R1 and R2 represents a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents.
As the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of R1 and R2, for example, a group removed one hydrogen atom from a hydrocarbon compound and as their examples, for example, a straight chained or cyclic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, an cycloalkyl group, an aryl group, an aralkyl group, etc. are exemplified.
Among them, C1-16 chained (straight chained or branched) or cyclic hydrocarbon group, etc. are preferred, and specifically,
(a) alkyl group [preferably, a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)],
(b) an alkenyl group [preferably, a lower alkenyl group (e.g., C2-6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.)],
(c) an alkynyl group [preferably, a lower alkynyl group (e.g., C2-6 alkynyl such as propargyl, ethynyl, butynyl, 1-hexynyl, etc.),
(d) a cycloalkyl group [preferably, a lower cycloalkyl group (e.g., C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl which may condense with a benzene ring optionally having 1 to 3 lower alkoxy groups (e.g., a C1-6 alkoxy group such as methoxy))],
(e) an aryl group (e.g., C6-14 aryl group such as phenyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, etc., preferably a phenyl group),
(f) an aralkyl group [preferably, a lower aralkyl group (e.g., C7-16 aralkyl group such as benzyl, phenetyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc, more preferably a benzyl group)], etc. are exemplified.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of R1 and R2, for example, (i) a halogen atom (e. g., fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (iii) a nitro group, (iv) a cyano group, (v) an optionally substituted lower alkyl group, (vi) an optionally substituted lower alkenyl group, (vii) an optionally substituted lower alkynyl group, (viii) a lower cycloalkyl group (e.g. , a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), which may be substituted by (a) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (b) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (c) a nitro group, (d) a cyano group, (e) an optionally substituted lower alkyl group, (f) an optionally substituted lower alkenyl group, (g) an optionally substituted lower alkynyl group, (h) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy, (j) an optionally halogenated lower alkylthio group, (k) a hydroxy group, (1) an amino group, (m) a mono-lower alkylamino group(e.g., amono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (n) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (p) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (q) a carboxyl group, (r) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) a carbamoyl group, (t) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (u) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (v) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (w) a sulfo group, (x) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (y) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (z) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (aa) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (bb) an oxo group, (cc) a thiocarbamoyl group, (dd) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (ff) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (gg) an aralkyl group (e.g., a C7-6 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc, (ix) an optionally substituted lower alkoxy, (x) an optionally halogenated lower alkylthio group, (xi) a hydroxy group, (xii) an amino group, (xiii) a mono-lower alkylamino group(e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xiv) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (xvi) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (xvii) a carboxyl group, (xviii) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix) a carbamoyl group, (xx) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (xxi) a di-lower alkyl-carbamoyl group (e.g.,. a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxii) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiii) a sulfo group, (xxiv) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (xxv) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.) which may be substituted by (a) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (b) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (c) a nitro group, (d) a cyano group, (e) an optionally substituted lower alkyl group, (f) an optionally substituted lower alkenyl group, (g) an optionally substituted lower alkynyl group, (h) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy, (j) an optionally halogenated lower alkylthio group, (k) a hydroxy group, (1) an amino group, (m) a mono-lower alkylamino group(e. g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (n) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (p) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (q) a carboxyl group, (r) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) a carbamoyl group, (t) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (u) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (v) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (w) a sulfo group, (x). a lower alkyl sulfonyl group (e.g., a C1-16 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (y) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (z) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (aa) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (bb) an oxo group, (cc) a thiocarbamoyl group, (dd) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (ff) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (gg) an aralkyl group (e.g., a C7-16aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc, (xxvi) an aralkyl group (e.g., a C7-15 ararlyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, naphthylmethyl, etc.) which may be substituted by (a) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (b) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (c) a nitro group, (d) a cyano group, (e) an optionally substituted lower alkyl group, (f) an optionally substituted lower alkenyl group, (g) an optionally substituted lower alkynyl group, (h) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy, (j) an optionally halogenated lower alkylthio group, (k) a hydroxy group, (1) an amino group, (m) a mono-lower alkylamino group(e. g., amono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) (n) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (p) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (q) a carboxyl group, (r) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) a carbamoyl group, (t) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (u) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (v) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (w) a sulfo group, (x) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (y) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (z) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (aa) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (bb) an oxo group, (cc) a thiocarbamoyl group, (dd) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (ff) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (gg) an aralkyl group (e.g., a C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc, (xxvii) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.) which may be substituted by (a) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (b) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (c) a nitro group, (d) a cyano group, (e) an optionally substituted lower alkyl group, (f) an optionally substituted lower alkenyl group, (g) an optionally substituted lower alkynyl group, (h) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy, (j) an optionally halogenated lower alkylthio group, (k) a hydroxy group, (1) an amino group, (m) a mono-lower alkylamino group(e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (n) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (p) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (q) a carboxyl group, (r) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) a carbamoyl group, (t) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (u) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (v) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (w) a sulfo group, (x) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (y) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (z) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (aa) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (bb) an oxo group, (cc) a thiocarbamoyl group, (dd) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (ff) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (gg) an aralkyl group (e.g., a C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-16 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc, (xxviii) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.) which may be substituted by (a) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (b) a lower alkylenedioxy group (e.g., C1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (c) a nitro group, (d) a cyano group, (e) an optionally substituted lower alkyl group, (f) an optionally substituted lower alkenyl group, (g) an optionally substituted lower alkynyl group, (h) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy, (j) an optionally halogenated lower alkylthio group, (k) a hydroxy group, (1) an amino group, (m) a mono-lower alkylamino group(e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (n) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (p) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (q) a carboxyl group, (r) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) a carbamoyl group, (t) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (u) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (v) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (w) a sulfo group, (x) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (y) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (z) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (aa) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (bb) an oxo group, (cc) a thiocarbamoyl group, (dd) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (ff) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (gg) an aralkyl group (e.g., a C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc, (xxix) an oxo group, (xxx) a thiocarbamoyl group, (xxxi) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxii) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (xxxiii) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (xxxiv) aryl-carbonyloxy (e.g., a C6-10 aryl-carbonyloxy group such as phenylcarbonyloxy, etc.), (xxxv) optionally substituted aminocarbonyl, (xxxvi) 5- or 6-membered heterocyclic group, (xxxvii) lower alkoxy-carbonyl-lower alkoxy-carbonyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkoxy-carbonyl such as methoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, etc.), (xxxviii) lower alkoxy-carbonyl-lower alkyl-carbamoyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkyl-carbamoyl such as methoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl, etc.), (xxxix) hydroxy-lower alkyl-carbamoyl (e.g., hydroxy-C1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, etc.), (xxxx) a lower alkoxy-carbonyl-carbamoyl group (e.g., a C1-6 alkoxy-carbonyl-carbamoyl group such as methoxycarbonylcarbamoyl, ethoxycarbonylcarbamoyl, etc.), (xxxxi) an arylsulfonamide group (e.g., a C6-14 arylsulfonamide group such as phenylsulfonamide, etc.), (xxxxii) an alkylsulfonamide group (e.g., a C1-6 alkylsulfonamide group such as methylsulfonamide, ethylsulfonamide, etc.), (xxxxiii) a carboxy-C1-6 alkyl-carbonyl-amino group (e.g., carbonylmethylcarbonylamino, carbonylmethylcarbonylamino, etc.), (xxxxiv) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl-amino group (e.g., methoxycarbonylmethylcarbonylamino, etc), (xxxxv) a C1-6 alkyl-carbonyloxy-C1-6 alkyl-carbonyl-amino group (e.g., methylcarbonyloxymethylcarbonylamino, etc.), (xxxxvi) a hydroxy-C1-6 alkyl-carbonyl-amino group (e.g., hydroxymethylcarbonylamino, etc.), (xxxxvii) a C6-14 aryl-C2-6 alkenyl-carbonylamido group (e.g., (4-hydroxy-3,5-methoxy)phenyl-ethylcarbonylamido) which may be substituted by hydroxy or/and C1-6 alkoxy (e.g., methoxy, ethoxy, etc.), etc. are used.
As the xe2x80x9coptionally substituted aminocarbonylxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, aminocarbonyl optionally having one or two (a) a halogen atom.(e.g., fluorine, chlorine, bromine, iodine, etc.), (b) an optionally substituted lower alkyl group, (c) an optionally substituted lower alkenyl group, (d) an optionally substituted lower alkynyl group, (e) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (f) an optionally substituted lower alkoxy, (g) an optionally halogenated lower alkylthio group, (h) a hydroxy group, (i) an amino group, (j) a mono-lower alkylamino group(e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (k) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (1) a 5- to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolodin-1-yl, etc.), (m) a lower alkylcarbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (n) a carboxyl group, (o) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (p) a carbamoyl group, (q) a mono-lower alkyl-carbamoyl group (e.g., a mono-C1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl), (r) a di-lower alkyl-carbamoyl group (e.g., a di-C1-6 alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (s) an aryl-carbamoyl group (e.g., C6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (t) a sulfo group, (u) a lower alkyl sulfonyl group (e.g., a C1-6 alkyl sulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.), (v) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.), (w) an aryloxy group (e.g., a C6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), (x) an aralkyloxy group (e.g., a C7-16 aralkyloxy group such as benzyloxy, etc.), (y) a thiocarbamoyl group, (z) a mono-lower alkyl-thiocarbamoyl group (e.g., a mono-C1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (aa) a di-lower alkyl-thiocarbamoyl group (e.g., a di-C1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (bb) an aryl-thiocarbamoyl group (e.g., a C6-10 aryl-thiocarbamoyl group such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.), (cc) an aralkyl group (e.g., a C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (dd) a lower alkoxy-carbonyl-lower alkyl group (e.g., a C1-6 alkoxy-carbonyl-C1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ee) a carboxyl-lower alkyl group (e.g., a carboxyl-C1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.), etc. are exemplified.
As the xe2x80x9c5- to 6-membered heterocyclic groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, a 5- to 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. are exemplified, of them pyridyl, etc. are preferred.
As the xe2x80x9clower alkyl group optionally having substituentsxe2x80x9d, xe2x80x9clower alkenyl group optionally having substituentsxe2x80x9d, xe2x80x9clower alkynyl group optionally having substituentsxe2x80x9d, lower alkoxy group optionally having substituentsxe2x80x9d and xe2x80x9coptionally halogenated lower alkylthio groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, the same those exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2 are used. Furthermore, as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d, a mono- or di-C1-6 alkyl-amino-methyleneaminosulfonyl group (e.g., dimethylaminomethyleneaminosulfonyl, etc.), etc. are also used.
As the xe2x80x9coptionally halogenated lower alkyl group xe2x80x9d, xe2x80x9coptionally halogenated lower alkenyl groupxe2x80x9d, xe2x80x9coptionally halogenated lower alkynyl groupxe2x80x9d and xe2x80x9coptionally halogenated lower alkylthio groupxe2x80x9d represented as the xe2x80x9coptionally substituted lower cycloalkyl groupxe2x80x9d, xe2x80x9coptionally substituted aryl groupxe2x80x9d, xe2x80x9coptionally substituted aryloxy groupxe2x80x9d and xe2x80x9coptionally substituted aralkyloxy groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, the same those exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2 are used.
As preferable xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc. are exemplified.
As preferable xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented as the other of the above R1 and R2, for example, (i) a lower cycloalkyl group (e.g., a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may be substituted by (a) a lower aklyl-carbonyl group (e.g., C1-6 alkyl-carbonyl group such as acetyl, propionyl, etc.), (b) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), etc. (ii) a carboxyl group, (iii) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (iv) an aryl group (e.g., a C6-10 aryl group such as phenyl, naphthyl, etc.) which may be substituted by (a) a lower alkoxy group (e.g., a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (b) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) or (c) a carboxyl group, etc. (v) aryl-carbonyloxy (e.g., a C6-10 aryl-carbonyloxy such as phenylcarbonyloxy, etc.), (vi) optionally substituted aminocarbonyl, (vii) 5- or 6-membered heterocyclic group, (viii) sulfonamido which may be substituted by lower alkyl optionally substituted by di-lower alkylamino(e.g., sulfonamide, sulfonamido-C1-6 alkyl which may be substituted by C1-6 alkyl optionally substituted by di-C1-6 alkylamino of dimethylaminomethylsulfonamido, etc.), (ix) lower alkoxy-carbonyl-lower alkoxy-carbonyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkoxy-carbonyl such as methoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, etc.), (x) a lower alkoxy group optionally substituted by (a) aminocarbonyl or (b) carboxyl (e.g., a C1-6 alkoxy group optionally substituted by aminocarbonyl such as methoxy, ethoxy, aminocarbonylmethoxy, carboxylmethoxy, etc.), (xi) a lower alkoxy-carbonyl-lower alkyl-carbamoyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkyl-carbamoyl such as methoxycarbonylmethylcarbamoyl, etc.), (xii) a hydroxy-lower alkyl-carbamoyl group (e.g., hydroxy-C1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, etc.), (xiii) a lower alkoxy-carbonyl-carbamoyl group (e.g., a C1-6 alkoxy-carbonyl-carbamoyl group such as methoxycarbonylcarbamoyl, ethoxycarbonylcarbamoyl, etc.) or (xiv) a cyano group, etc. are exemplified.
As the other of R1 and R2, preferably, a hydrogen atom, a cyano group, a C1-6 alkyl group optionally having substituents, or a C3-6 cycloalkyl group, etc. are exemplified, particularly, a hydrogen atom, a cyano group, methyl, tert-butyl, cyclohexyl, xe2x80x94CH2CO2Me, xe2x80x94(CH2)2CO2Et, xe2x80x94(CH2)3CO2Et, xe2x80x94C(Me)2CO,2Et, xe2x80x94C(Me)2CO2Me, xe2x80x94C(Me)2CO2H, xe2x80x94(CH2)4CO2Et, xe2x80x94CH2CO2H, xe2x80x94(CH2)2OCH2CONH2, xe2x80x94(CH2)2OCH2CO2H, xe2x80x94(CH2)2CO2H, xe2x80x94(CH2)4CO2H, xe2x80x94(CH2)2OCOPh, xe2x80x94CH2CONMeCH2CH2Ph, xe2x80x94CH2Ph, xe2x80x94(CH2)2Ph, xe2x80x94(CH2)3Ph, xe2x80x94(CH2)2C(Me)2CO2Et, xe2x80x94CH2C6H4(2-CO2Me), xe2x80x94CH2C6H4(3-CO2Me), xe2x80x94CH2C6H4(4-CO2Me), xe2x80x94CH2C6H4(2-CO2H), xe2x80x94CH2C6H4(3-CO2H), xe2x80x94(CH2)2C(Me)2SO2NHCHNMe2, xe2x80x94(CH2)2C(Me)2SO2NH2, xe2x80x94CH2CO2CH2CO2Me, xe2x80x94CH2CON(Me)CH2CO2Et, xe2x80x94CH2CON(Me)CH2CO2H, xe2x80x94CH2CONHC(Me)2CO2Et, xe2x80x94CH2CONHCH2CO2Me, xe2x80x94CH2CONHCH2CO2H, xe2x80x94CH2CONH(CH2)2CO2Et, xe2x80x94CH2CONH(CH2)2CO2H, xe2x80x94(CH2)2CONHCO2Me, xe2x80x94(CH2)2CONHCO2H, xe2x80x94(CH2)4CN, 
etc. are exemplified (Me represents methyl, Et represents ethyl, Ph represents phenyl).
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cC1-6 alkyl group optionally having substituentsxe2x80x9d and xe2x80x9cC3-6 cyclo alkyl group optionally having substituentsxe2x80x9d represented as preferable examples of the other of the R1 and R2, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by the other of the above R1 and R2 are exemplified, and as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9ca C3-6 cycloalkyl group optionally having substituentsxe2x80x9d, the same those represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above Ar1 and Ar2 , etc. are preferred.
Of the above-mentioned, as R1 and R2, it is preferred that any one of them represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent a phenyl; ring B represents 
X represents a C1-6 alkylene group; Y represents a bond or an oxygen atom; R3 represents a hydrogen atom or a hydroxy group), and the other represents (1) a hydrogen atom, (2) a cyano group, (3) a C1-16 alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a carboxyl group, (iii) a C1-6 alkoxy-carbonyl group, (iv) a 5- to 6-membered nitrogen-containing heterocyclic group, (v) a carbamoyl group optionally having substituents selected from C7-15 aralkyl, carboxyl-C1-6 alkyl and C1-6 alkoxycarbonyl-C1-6 alkyl, (vi) C6-14 aryl-carbonyloxy group, (vii) a sulfamoyl, (viii) a mono- or di-C1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) a C1-6 alkoxy group optionally having carboxyl or carbamoyl and (x) cyano, (4) a C3-7 cycloalkyl group optionally having carboxyl or C1-6 alkoxycarbonyl, (5) a C6-14 aryl group or (6) a C7-‥aralkyl group optionally having substituents selected from C1-6 alkoxy, carboxyl or C1-6 alkoxy-carbonyl.
Furthermore, as R1 and R2, it is preferred that any one of them represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent a phenyl; ring B represents 
X represents a C1-6 alkylene group; Y represents an oxygen atom; R3 represents a hydrogen atom or a hydroxy group), and the other represents (1) a hydrogen atom, (2) a cyano group, (3) a C1-6 alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a C1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) cyano or (4) a C3-7 cycloalkyl group optionally having C1-6 alkoxycarbonyl.
Particularly, as R1 and R2, it is preferred that any one of them represents a group represented by the formula: 
(wherein Ar1 and Ar2 represent a phenyl; ring B represents 
X represents a C1-6 alkylene group; Y represents an oxygen atom; R3 represents a hydrogen atom) and the other represents a C1-6 alkyl group optionally having carboxyl.
In the above-mentioned formula (I), ring A represents a homocycle optionally having substituents or a nitrogen-containing heterocycle optionally having substituents.
The xe2x80x9chomo or (nitrogen-containing)heterocyclexe2x80x9d represented as the ring A have any number (preferably 1 to 5, more preferably 1 to 3) of substituents at the position where substitution is possible, and when the number of substituents is not less than 2, each substituent is same or different, and adjacent two substituents may form a ring by binding to each other.
As examples in the case that adjacent two substituents form a ring by binding to each other, for example,
(1) a 3- to 10-membered cyclic hydrocarbon (preferably 5-to 6-membered cyclic hydrocarbon),
(2) a 3- to 9-membered aromatic nitrogen-containing heterocycle (preferably 5- to 6-membered aromatic nitrogen-containing heterocycle) which contains one or two kinds of and not less than one (for example, 1 to 4, preferbaly 1 to 3) hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and nitrogen, or
(3) a 3- to 9-membered non-aromatic nitrogen-containing heterocycle (preferably 5- to 6-membered non-aromatic nitrogen-containing heterocycle) which contains one or two kinds of and not less than one (for example, 1 to 4, preferably 1 to 3) hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and nitrogen, etc. are exemplified.
More specifically, as the xe2x80x9ccyclic hydrocarbonxe2x80x9d of the above-mentioned (1), for example, C6-10 aryl (e.g., benzene, etc.), C3-10 cycloalkene (e.g., cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C3-10 cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. are exemplified. Among them, for example, a 5- to 6-membered homocycle such as benzene, cyclopentane, cyclohexane rings, etc. are preferred, and particularly a benzene ring is preferred.
As the xe2x80x9caromatic nitrogen-containing heterocyclexe2x80x9d of the above-mentioned (2), for example, a 5- to 9-membered (preferably 5- to 6-membered) aromatic nitrogen-containing heterocycle which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon and nitrogen atom such as pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole and isoxazole, etc. are exemplified.
As the xe2x80x9cnon-aromatic nitrogen-containing heterocyclexe2x80x9d of the above-mentioned (3), for example, a 5- to 9-membered (preferably 5- to 6-membered) non-aromatic nitrogen-containing heterocycle which contains 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon and nitrogen atom such as tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, thimorpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole rings, etc. are exemplified.
The xe2x80x9chomocyclexe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by ring A means a 3- to 10-membered cyclic hydrocarbon, and preferably a 5- or 6-membered cyclic hydrocarbon, etc. are included. Specifically, benzene, C3-10 cycloalkene (e.g., cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C3-10 cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. are exemplified. Among them, for example, a 5- to 6-membered homocycle such as benzene, cyclopentane, cyclohexane rings, etc. are preferred, and particularly a benzene ring is preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by ring A, the same those as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by the other of the above-mentioned R1 and R2, etc. are exemplified. Among them, (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (ii) a nitro group, (iii) an optionally halogenated lower alkyl group, (iv) an amino group, (v) a mono-lower alkylamino group (e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (vi) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (vii) a carboxyl group, (viii) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (ix) sulfonamido which may be substituted by lower alkyl optionally having di-lower alkylamino (e.g., sulfonamido, sulfonamido-C1-6 alkyl which may be substituted by C1-6 alkyl optionally substituted by di-lower alkylamino of dimethylaminomethylsulfonamido, etc.), (x) lower alkoxy-carbonyl-lower alkyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkyl such as methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, etc.), (xi) hydroxy-lower alkyl-carbamoyl (e.g., hydroxy-C1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl hydroxyethylcarbamoyl, etc.), (xii) phenylsulfonamido, (xiii) a hydroxy group and (xiv) a lower alkoxy group optionally having substituents, etc. are exemplified.
As the xe2x80x9coptionally halogenated lower alkyl groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by ring A, the same those as the xe2x80x9coptionally halogenated lower alkyl groupxe2x80x9d exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above-mentioned Ar1 and Ar2 are used.
As the xe2x80x9clower alkoxy group optionally having substituentsxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by ring A, the same those as the xe2x80x9clower alkoxy group optionally having substituentsxe2x80x9d exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above-mentioned Ar1 and Ar2, and as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9clower alkoxy group optionally having substituentsxe2x80x9d, for example, a lower alkoxy group (e.g., a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) optionally having 1 or 2 substituents selected from (i) a lower alkoxy-carbonyl group (e.g. C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, etc.) and (ii) an aromatic group (for example, the xe2x80x9caromatic groupxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above-mentioned Ar1 and Ar2, etc.), etc. are exemplified.
As the xe2x80x9cnitrogen-containing heterocyclexe2x80x9d of the xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d represented by ring A, for example, a 3- to 13-membered nitrogen-containing heterocycle which contains one nitrogen atom and may further contain, for example, 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, etc. are exemplified.
Specifically, for example, a 3- to 9-membered (more preferably 3- to 6-membered) nitrogen-containing heterocyclic group such as 
etc. are preferred. Among them, 
etc. are particularly preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d represented by ring A, for example, the same those exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by the above-mentioned ring A, etc. are used.
As ring A, a benzene ring optionally having substituents, a pyridine ring optionally having substituents and a pyrazine ring optionally having substituents, etc. are preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cbenzene ring optionally having substituentsxe2x80x9d, xe2x80x9cpyridine ring optionally having substituentsxe2x80x9d and xe2x80x9cpyrazine ring optionally having substituentsxe2x80x9d represented as preferable ring A, for example, the same those exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chomocycle optionally having substituentsxe2x80x9d represented by the above-mentioned ring A or the xe2x80x9cnitrogen-containing heterocycle optionally having substituentsxe2x80x9d, etc. are used.
As ring A, (1) an unsubstituted benzene ring or (2) a benzene ring having 1 to 3 substituents selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (ii) a nitro group, (iii) an optionally halogenated lower alkyl group, (iv) an amino group, (v) a mono-lower alkylamino group (e.g., a mono-C1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (vi) a di-lower alkylamino group (e.g., a di-C1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (vii) a carboxyl group, (viii) a lower alkoxy-carbonyl group (e.g., C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (ix) sulfonamido which may by substituted by lower alkyl optionally having di-lower alkylamino (e.g., sulfonamido, sulfonamido-C1-6 alkyl which may be substituted by C1-6 alkyl optionally substituted by di-lower alkylamino of dimethylaminomethylsulfonamido, etc.), (x) lower alkoxy-carbonyl-lower alkyl (e.g., C1-6 alkoxy-carbonyl-C1-6 alkyl such as methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, etc.), (xi) hydroxy-lower alkyl-carbamoyl (e.g., hydroxy-C1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, etc.), (xii) phenylsulfonamido, (xiii) a hydroxy group and (xix) a lower alkoxy group optionally having substituents, etc. are exemplified.
As the xe2x80x9coptionally halogenated lower alkyl groupxe2x80x9d and xe2x80x9coptionally halogenated lower alkoxy groupxe2x80x9d represented as the xe2x80x9csubstituentsxe2x80x9d of the ring A, the same those as the xe2x80x9coptionally halogenated lower alkyl groupxe2x80x9d and xe2x80x9coptionally halogenated lower alkoxy groupxe2x80x9d exemplified as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic group optionally having substituentsxe2x80x9d represented by the above-mentioned Ar1 and Ar2, etc. are exemplified.
In the above-mentioned formula (I), D and E are the same or different and represent, independently, an oxygen atom or a sulfur atom. As D and E, the case where both represent an oxygen atom is preferred.
As preferable examples of the compound (I) of the present invention, the following compounds are exemplified.
(I) Compound (Ia)
A compound wherein ring A is a C6-14 aryl ring optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a nitro group, (iii) a C1-6 alkyl group optionally having carboxyl or C1-6 alkoxy-carbonyl, (iv) C1-6 alkoxy group, (v) a hydroxy group, (vi) an amino group, (vii) a mono- or di-C1-6 alkylamino group, (viii) a carboxyl group, (ix) a C1-6 alkoxy-carbonyl group, (x) a 5-to 6-membered heterocyclic group which contains one or two kinds of and 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, (xi) C1-6 alkylsulfonamido, (xii) a carboxy-C1-6 alkyl-carbonyl-amino group, (xiii) a C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl-amino group, (xiv)a C1-6 alkyl-carbonyl-oxy-C1-6 alkyl-carbonyl-amino group and (xv) C6-14 aryl-C2-6 alkenyl-carbonylamido group optionally substituted by hydroxy or/and C1-6 alkoxy; D and E are an oxygen atom; one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X represents a C1-6 alkylene group; Y represents a bond or an oxygen atom; R3 represents a hydrogen atom or a hydroxy group); and the other is (1) a hydrogen atom, (2) a cyano group, (3) a C1-6alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a carboxyl group, (iii) a C1-6 alkoxy-carbonyl group, (iv) a 5- to 6-membered nitrogen-containing heterocyclic group, (v) a carbamoyl group optionally having substituents selected from C7-15 aralkyl, carboxyl-C1-6 alkyl and C1-6 alkoxycarbonyl-C1-6 alkyl, (vi) C6-14 aryl-carbonyloxy group, (vii) a sulfamoyl, (viii) a mono- or di-C1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) a C1-6 alkoxy group optionally having carboxyl or carbamoyl and (x) cyano, (4) a C3-7 cycloalkyl group optionally having carboxyl or C1-6 alkoxycarbonyl, (5) a C6-14 aryl group or (6) a C7-15 aralkyl group optionally having substituents selected from C1-6 alkoxy, carboxyl or C1-6 alkoxy-carbonyl.
(II) Compound (Ib)
A compound wherein ring A is a benzene ring optionally having (i) a halogen atom or (ii) C1-6 alkoxy-carbonyl; D and E are an oxygen atom; one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X is a C1-6 alkylene group, Y is an oxygen atom, R3is a hydrogen atom or a hydroxy group); and the other is (1) a hydrogen atom, (2) a cyano group, (3) a C1-6 alkyl group optionally having substituents selected from the group consisting of (i) a halogen atom, (ii) a C1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) cyano or (4) a C3-7 cycloalkyl group optionally having C1-6 alkoxycarbonyl.
(III) Compound (Ic)
A compound wherein ring A is a benzene ring optionally having a halogen atom; D and E are an oxygen atom; one of R1 and R2 is a group represented by the formula: 
(wherein Ar1 and Ar2 are a phenyl group, ring B is 
X is a C1-6 alkylene group, Y is an oxygen atom, R3is a hydrogen atom); and the other is a C1-6 alkyl group optionally having carboxyl.
(IV) Compound (Id)
{circumflex over (1)} 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-valeric acid or a salt thereof,
{circumflex over (2)} 2-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-yl]isobutyric acid or a salt thereof (particularly, a salt of hydrochloride), and
{circumflex over (3)} 2-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-fluoro-1,2,3,4-tetrahydroquinazoline-3-yl]isobutyric acid or a salt thereof (particularly, a salt of hydrochloride).
A method for producing the compound (I) of the present invention or its salt is described below.
The compound (I) of the present invention or its salt wherein R1 is a group represented by the formula: 
may for example be produced by Method A described below or an equivalent.
(Method A)
A method which reacts a compound represented by the formula: 
[wherein Q1 represents a leaving group and other symbols represent the same meanings as defined above], or a salt thereof with a compound represented by the formula: 
[wherein Q2 represents a reactive group, R2xe2x80x2 represents a hydrogen atom, a cyano group or a hydrocarbon group optionally having substituents and other symbols represent the same meanings as defined above], or a salt thereof.
As the leaving group represented by Q1, for example, alkali metals such as sodium, potassium, etc. are used. And, Q1 may be a hydrogen atom.
As the reacting group represented by Q2, for example, a halogen atom (e.g., chlorine, bromine, iodine, etc.), C6-10 arylsulfonyloxy (e.g., benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), C1-4 alkyl-sulfonyloxy (e.g., methanesulfonyloxy, etc.), etc. are used.
As the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by the above mentioned R2xe2x80x2, for example, the same those as the xe2x80x9chydrocarbon group optionally having substituentsxe2x80x9d represented by one of the above mentioned R1 and R2, etc. are used.
In the Method A shown above, about 1.1 to about 2.0 moles, preferably about 1.2 to about 1.5 moles of the compound (IIa) or its salt is usually used per 1 mole of the compound (III) or its salt.
The reaction described in Method A shown above is conducted preferably in the presence of a base, and as the base,
(1) for example, an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) for example, an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4). Among them, potassium carbonate or triethylamine is preferred.
The amount of the base employed is usually about 1.1 moles to about 2.0 moles per 1 mole of the compound (III) or its salt, preferably about 1.2 moles to about 1.5 moles per 1 mole of the compound (III) or its salt.
The reaction described in Method A shown above is conducted also in an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine, etc.
Among them, those preferred are acetonitrile and N,N-dimethylformamide, etc.
Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water.
The amount of a solvent employed is about 5 ml to about 50 ml, preferably about 20 ml to about 30 ml per 1 g of the compound (IIa).
And, when a reactive group represented by Q2 is chlorine, etc., it is preferred to add sodium iodide, etc. to the solvent.
Preferred examples of the base and the solvent employed in the reaction described in Method A shown above, for example,
(1) triethylamine as a base and acetonitrile as a solvent,
(2) triethylamine as a base and N,N-dimethylformamide as a solvent; or,
(3) potassium carbonate as a base and N,N-dimethylformamide as a solvent.
The reaction temperature usually ranges from about 10xc2x0 C. to about 150xc2x0 C., preferably from room temperature (about 10xc2x0 C. to about 30xc2x0 C.) to about 100xc2x0 C.
The reaction time usually ranges from about 12 hours to about 36 hours, preferably about 15 hours to about 28 hours.
Methods for producing the compounds (IIa), (III) and their salts in Method A shown above are described below.
The compound (IIa) or its salt described above can be produced by a method described, for example, in {circumflex over (1)} EP-A-0399414, {circumflex over (2)} J.Org.Chem.,26,4084 (1961), {circumflex over (3)} Eur.J.Med.Chem., 26, 69 (1991) or {circumflex over (4)} J.Med.Chem., 38, 2472 (1995) or equivalent methods.
The compound (III) or. its salt is for example produced by a method described in Scheme A shown below or equivalent. 
[In the compound [III] to [VII] of the above mentioned scheme A, each symbol represents the same meanings as mentioned above.]
Reaction Step 1 is a process for producing the compound [VI] or its salt by reacting the compound [IV] or the compound [V] or their salts with R2xe2x80x2xe2x80x94NH2 (compound [VIII]) (R2xe2x80x2 is defined as above) or its salt.
When R2xe2x80x2 is a hydrogen atom, etc., however, it is preferable that the group represented by xe2x80x94NHR2xe2x80x2 in the compound [VI] shown above is protected with a protective group such as 4-methoxybenzylamine, 4-methoxyphenylamine, 4-(4-methoxy)phenylamine or 2,4-dimethoxybenzylamine (4-methoxybenzylamine being particularly preferred), and a method for protection or deprotection may be one known per se [T. W. Green and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, 2nd. ed., John Willey and Sons, Inc., (1991)] or equivalent. When producing the compound [I] of the present invention or its salt, it is preferable that the above mentioned protective group is deprotected in the process in Reaction Step 3 described above.
As specific methods for deprotection, a method which admixes the compound [III] or its salt which has been protected with a protective group listed above, in a solvent mixture of acetonitrile and water (usually about 20 ml to about 40 ml, preferably about 30 ml to about 35 ml (usually acetonitrile:water=5:1) per 1 g of the protected compound), with ammonium cerium (IV) nitrate (usually about 1.2 moles to about 2.0 moles, preferably about 1.5 moles), etc. are exemplified. In Reaction Step 1 described above, about 1.1 moles to about 1.5 moles, preferably about 1.2 moles of the compound [VIII] or its salt is usually used per 1 mole of the compound [IV] or its salt or the compound [V] or their salts.
The compound [IV] and the compound [V] or their salts may be commercially available or may be synthesized by a method described in {circumflex over (1)} Synthesis, 505 (1980) or {circumflex over (2)} Adv. Heterocycl. Chem. 28, 127 (1981) or equivalent.
A reaction in Reaction Step 1 described above is, for example, conducted also in an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine, etc. and among them, tetrahydrofuran, N,N-dimethylformamide, etc. are exemplified as a preferable solvent.
When using the compound [IV] or its salt as a starting material, it is preferable to use tetrahydrofuran and the like as a solvent, while when using the compound [V] or its salt as a starting material, it is preferable to use N,N-dimethylformamide and the like as a solvent. Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water. The amount of the solvent employed per 1 g of the compound (IV) is about 10 ml to about 50 ml, preferably about 10 ml to about 15 ml.
The reaction described in Reaction Step 1 described above may be conducted in the presence of a base, and especially when using the compound [V] or its salt as a starting material, it is usually preferred to conduct the reaction in the presence of a base. As the base,
(1) for example, an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) for example, an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4). Among them, triethylamine is exemplified as a preferable base.
The amount of the base employed is usually about 1.2 moles to about 3.0 moles, preferably about 2.0 moles to about 2.5 moles per 1 mole of the compound (V) or its salt.
When the compound [V] or its salt is employed as a starting material in Reaction Step 1 shown above, it is preferable to use about 1.2 equivalents of a condensing agent relative to the compound [V] or its salt, and as the condensing agent, for example, diethyl cyanophosphonate (DEPC), diphenylphosphoric azide (DPPA), N,N-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 2-bromo-1-methylpyridinium iodide, 2-chloro-1-methylpyridinium iodide or 2,2-dithiopyridine and the like are used, and DEPC is preferably used.
The reaction time of the reaction step described above ranges usually from about 15 hours to about 36 hours, preferably about 15 hours to about 24 hours, while the reaction temperature ranges usually from room temperature (about 10xc2x0 C. to 30xc2x0 C.) to about 100xc2x0 C., preferably from room temperature to about 60xc2x0 C.
The Reaction Step 2 is a process for producing the compound [VII) or its salt by subjecting the compound [VI] or its salt to a ring-closure reaction by means of subjecting a reaction with N,N-carbonyldiimidazole (CDI) or ethyl chloroformate and the like.
In Reaction Step 2 shown above, about 1.0 mole to about 1.5 moles, preferably about 1.2 moles of Q3xe2x80x94COxe2x80x94Q4 (wherein each of Q3 and Q4 is a leaving group) is usually used per 1 mole of the compound [VI] or its salt.
As the leaving group represented by Q3 or Q4, same or different from each other, (1) a hydrogen atom, (2) a halogen atom (fluorine, chlorine, bromine, iodine and the like), (3) a lower alkyl group (e.g., C1-6 alkyl group such as methyl, ethyl, propyl and the like) optionally substituted with a halogen atom (fluorine, chlorine, bromine, iodine and the like), (4) a lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, propoxy and the like) optionally substituted with a halogen atom (fluorine, chlorine, bromine, iodine and the like), or (5) a 5- to 6-membered heterocyclic group (e.g., imidazolyl and the like), etc. are exemplified, and as the Q3xe2x80x94COxe2x80x94Q4 (wherein Q3 and Q4 are defined as above), specifically N,N-carbonyldiimidazole (CDI), ethyl chlorformate or triphosgene and the like (preferably CDI and ethyl chloroformate and the like), etc. are exemplified.
The reaction in Reaction Step 2 shown above can be conducted in an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine, and, among them, those preferred are ethanol, N,N-dimethylformamide, pyridine and the like.
N,N-dimethylformamide is a preferred solvent when the compound [VI] or its salt is reacted with CDI, while pyridine is a preferred solvent when the compound [VI] or its salt is reacted with ethyl chloroformate. Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water. The amount of the solvent employed is about 3 ml to about 10 ml, preferably about 3 ml to about 7 ml per 1 g of the compound (VI).
When the compound [VI] or its salt has a bulky substituent such as isobutyrate group (xe2x80x94C(Me)2CO2Et) as a group R2xe2x80x2 in the reaction described in Reaction Step 2 shown above, the compound [VII] is obtained through a conversion into a carbamate form by a reaction with ethyl chloroformate and the like, followed by a ring-closure reaction of the carbamate form in the presence of a base, and when describing more accurately, further followed by a neutralization with an acid.
As the base,
(1) for example, an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) for example, an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4). Among them, sodium ethoxide, etc. are exemplified as a preferable base.
The amount of the base employed is usually about 1.0 moles to about 2.0 moles, preferably about 1.0 moles to about 1.2 moles per 1 mole of the compound [VI] or its salt.
The reaction temperature of Reaction Step 2 shown above ranges usually from room temperature (about 10xc2x0 C. to about 30xc2x0 C.) to about 180xc2x0 C., preferably from 120xc2x0 C. to 150xc2x0 C., while the reaction time ranges usually from 8 hours to 24 hours, preferably 15 hours to 24 hours.
The ring-closure reaction of a carbamate form when the compound [VI] or its salt, in the reaction described in Reaction Step 2 shown above, has a bulky substituent such as isobutyrate group (xe2x80x94C(Me)2CO2Et) as a group R2xe2x80x2 is performed usually under reflux at a reaction temperature ranging from about 100xc2x0 C. to about 120xc2x0 C. The reaction time usually ranges from about 8 hours to about 24 hours, preferably about 12 hours to about 18 hours. And, as the solvent, for example, an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitriles such as acetonitrile and the like,
(5) amides. such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine, etc. are exemplified, and the amount of the solvent employed is usually about 10 ml to about 30 ml, preferably about 15 ml to about 20 ml per 1 g of the compound [VI].
The Reaction Step 3 is a process for producing the compound [III] or its salt by reacting compound [VII] or its salt with Q2xe2x80x2xe2x80x94Xxe2x80x94Q2(wherein Q2 and X are defined as above, and Q2xe2x80x2 is same to Q2) or its salt.
The reaction in Reaction Step 3 shown above can be conducted in an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine, and, among them, N,N-dimethylformamide and the like are exemplified as a preferable solvent.
Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water. The amount of the solvent employed is about 5 ml to about 20 ml, preferably about 5 ml to about 15 ml per 1 g of the compound (VII).
The reaction described in Reaction Step 3 shown above may also be conducted in the presence of a base. As the base,
(1) for example, an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) for example, an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like, etc. are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4). Among them, sodium hydride is exemplified as a preferable base.
The amount of the base employed is usually about 1.1 moles to about 2.0 moles, preferably about 1.2 moles to about 1.5 moles per 1 mole of the compound [VII] or its salt.
The reaction temperature of Reaction Step 3 shown above ranges usually from 10xc2x0 C. to 30xc2x0 C., preferably from 15xc2x0 C. to 25xc2x0 C., while the reaction time ranges usually from 8 hours to 24 hours, preferably 15 hours to 24 hours.
When R2xe2x80x2 is a hydrogen atom (such as a compound in Reaction Step 3 in which 4-methoxybenzyl group is deprotected) in the compound [III] described above, the compound [I] of the present invention or its salt can be produced by a reaction (Reaction Step 4) of the compound [III] with a compound represented by the formula: R2xe2x80x2-L1[XI] (wherein R2xe2x80x2 is defined as above (but other than hydrogen atom), L1 is a halogen atom (e.g., chlorine, bromine, iodine and the like)) in the presence of a suitable base (preferably potassium carbonate and the like) in a suitable solvent (preferably N,N-dimethylformamide) with using NaI and the like if necessary.
As the solvent employed in Reaction Step 4 shown above, for example, an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like, etc. are exemplified, and, among them, N,N-dimethylformamide and the like are preferably used.
Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water. The amount of the solvent employed is about 10 ml to about 30 ml, preferably about 15 ml to about 20 ml per 1 g of the compound (I).
As the base employed in Reaction Step 4 shown above,
(1) an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4).
The amount of the base employed is usually about 1.1 moles to about 2.0 moles, preferably about 1.1 moles to about 1.5 moles per 1 mole of the compound [I] or its salt.
The reaction temperature of Reaction Step 4 shown above ranges usually from 10xc2x0 C. to 100xc2x0 C., preferably from 20xc2x0 C. to 60xc2x0 C., while the reaction time ranges usually from 12 hours to 36 hours, preferably 16 hours to 30 hours.
When R2 is a group represented by the formula: 
in compound (I) of the present invention or its salt, the production may follow Method B shown below or equivalent.
(Method B)
A production method in which a compound represented by the formula: 
[wherein each symbol is defined as above] or its salt is reacted with Q3xe2x80x94COxe2x80x94Q4 (each of Q3 and Q4 is a leaving group) whereby subjecting to a ring-closure reaction.
As the leaving group represented by each of Q3 and Q4, the same those as described above are used.
A ring-closure reaction in Method B may be conducted similarly to the ring-closure reaction in Reaction Step 2 in Method A described above, and preferably the compound [IX] and CDI (usually in an amount of about 1.1 moles to about 1.5 moles, preferably about 1.2 moles per 1 mole of the compound [IX]) are reacted in N,N-dimethylformamide (usually in a volume of about 10 ml to 20 ml, preferably about 15 ml per 1 g of the compound [IX]).
The compound [IX] described above is produced by reacting the compound [IV] or its salt described in Scheme A shown above with a compound represented by the formula: 
[wherein each symbol is defined as above] or its salt (Method C).
The compound [X] described above or its salt may be synthesized by a method described, for example, in {circumflex over (1)} J.Heterocycl. Chem. 22, 1035(1985) or {circumflex over (2)} Chem. Pham. Bull., 37 (1), 100(1989) or equivalent.
In Method C shown above, about 1.1 moles to about 1.5 moles, preferably about 1.2 moles of the compound (X) or its salt is usually used per 1 mole of the compound (IV) or its salt.
The reaction described in Method C shown above may be conducted also in the presence of a base, and as the base
(1) for example, an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium and the like,
(2) for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like,
(3) for example, an organic base such as triethylamine, pyridine, diethylisopropylamine and the like,
(4) a metal alcholate such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like are used, and an alkaline metal such as metal lithium, metal potassium, metal sodium and the like are used instead of the base described in (1) to (4). Among them, potassium carbonate or triethylamine and the like are exemplified as a preferable base.
The amount of the base employed is usually about 1.1 moles to about 1.5 moles, preferably about 1.2 moles per 1 mole of the compound [IV] or its salt.
A reaction described in Method C shown above is conducted also in an inert solvent such as
(1) alcohols such as methanol, ethanol, propanol and the like,
(2) ethers such as diethyl ether, dioxane, tetrahydrofuran and the like,
(3) hydrocarbons such as pentane, hexane, benzene, toluene, xylene and the like,
(4) nitrites such as acetonitrile and the like,
(5) amides such as N,N-dimethylformamide, N,N-dimethylacetoamide, hexamethylphosphoric triamide and the like,
(6) sulfoxides such as dimethyl sulfoxide and the like,
(7) aromatic amines such as pyridine.
Among them, tetrahydrofuran, N,N-dimethylformamide and the like are exemplified as a preferable solvent.
Each of these solvents can be used alone, or in combination with one or more of other solvents in suitable ratios, or with water. The amount of the solvent employed is about 20 ml to about 40 ml, preferably about 25 ml to about 30 ml per 1 g of the compound (IV).
The reaction temperature usually ranges from about 10xc2x0 C. to about 100xc2x0 C., preferably from about 20xc2x0 C. to about 25xc2x0 C.
The reaction time usually ranges from about 12 hours to about 36 hours, preferably about 16 hours to about 24 hours.
The compound (I) or its salt thus obtained, when it is in a free form, can be converted by a standard method to a salt, or when in the form of a salt can be converted by a standard method into a free form or other salts. The compound (I) or its salt thus obtained can be isolated and purified by a known method such as solvent extraction, liquid phase conversion, partition, salting-out, crystallization, recrystallization, chromatography and the like. When the compound (I) or its salt includes any optical isomer, a standard optical resolution method is employed to resolve it into R and S forms.
In each reaction of the present invention and in each reaction for synthesizing each starting material, an amino group, a carboxyl group and a hydroxyl group, each as a substituent, if any, in a starting material may be protected by a protective group employed customarily in peptide chemistry, which may be deprotected after reaction if necessary in order to yield an intended compound.
As a protective group for an amino group, formyl, an optionally substituted C1-6 alkylcarbonyl (e.g., acetyl, ethylcarbonyl and the like), phenylcarbonyl, an optionally substituted C1-6 alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl and the like), optionally substituted phenyloxycarbonyl, an optionally substituted C7-10 aralkylcarbonyl (e.g., benzylcarbonyl and the like), optionally substituted trityl, optionally substituted phthaloyl or optionally substituted N,N-dimethylaminomethylene, optionally substituted 4-methoxybenzylamine, optionally substituted 4-methoxyphenylamine, optionally substituted 4-(4-methoxy)phenylamine or optionally substituted 2,4-dimethoxybenzylamine and the like are used. As the substituents for them, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), a C1-6 alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), nitro group and the like are used, and the number of the substituents is one to about three.
As a protective group for a carboxyl group, an optionally substituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl and the like), optionally substituted phenyl, optionally substituted trityl or optionally substituted silyl and the like are used. As substituents for them, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), formyl, a C1-6 alkylcarbonyl (e.g., acetyl, ethylcarbonyl, butylcarbonyl and the like), nitro group and the like are used, and the number of the substituents is one to about three.
As a protective group for a hydroxyl group, an optionally substituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl and the like), optionally substituted phenyl, an optionally substituted C7-10 aralkyl (e.g., benzyl and the like), formyl, an optionally substituted C1-6 alkylcarbonyl (e.g., acetyl, ethylcarbonyl and the like), optionally substituted phenyloxycarbonyl, optionally substituted benzoyl, an optionally substituted C7-10 aralkylcarbonyl (e.g., benzylcarbonyl and the like), optionally substituted pyranyl, optionally substituted furanyl or optionally substituted silyl and the like are used. As substituents for them, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), a C1-6 alkyl (e.g., methyl, ethyl, n-propyl and the like), phenyl, a C7-10 aralkyl (e.g., benzyl), nitro group and the like are used, and the number of the substituents is one to about four.
A method for deprotecting a protective group is, or may be in accordance with one known per se, and may employ a treatment with an acid, a base, a reducing agent, UV, hydrazine, phenylhydrazine, sodium N-methylthiocarbamate, tetrabutylammonium fluoride, palladium acetate and the like.
And, a salt of the compound (I) is preferably one which is pharmaceutically acceptable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid.
Preferred examples of a salt with an inorganic base are an alkali metal salt (e.g., sodium salt, potassium salt and the like), an alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like), an aluminum salt, an ammonium salt and the like.
Preferred examples of a salt with an organic base are a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine and the like.
Preferred examples of a salt with an inorganic acid are a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferred examples of a salt with an organic acid are a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid and the like.
Preferred examples of a salt with a basic amino acid are a salt with arginine, lysine, ornitine and the like.
Preferred examples of a salt with a acidic amino acid are a salt with aspartic acid, glutamic acid and the like. When an intended compound is obtained as a free form, it may be converted into a salt by a standard method, and when an intended compound is obtained as a salt, it may be converted into a free form by a standard method.
The compound (I) of the present invention or its salt may be a hydrate or an anhydride.
Since the compound (I) of the present invention or its salt has excellent anti-allergic action, anti-histaminic action, anti-inflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis-inhibiting action and the like and has a lower toxicity (acute toxicity: LD50 greater than 2 g/kg), it can safely be used as an anti-allergic agent in mammals (e.g., human, mouse, dog, rat, cattle and the like). Moreover, the compound (I) or its salt also has an eosinophil chemotaxis-inhibiting effect in combination with an anti-histaminic action, and can be used for preventing or treating an allergic disease such as urticaria (e.g., chronic urticaria), atopic dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitive pneumonitis and the like, a dermal disease such as eczema, herpetic dermatitis, psoriasis and the like, a respiratory disease such as eosinophilic pneumonia (PIE syndrome), asthma (e.g., bronchial asthma) and the like in mammals as discussed above. Among them, it is used as an agent for preventing or treating an allergic disease, asthma (e.g., bronchial asthma), allergic conjunctivitis, allergic rhinitis, urticaria (e.g., chronic urticaria) and atopic dermatitis. The way of administration may be oral or parenteral.
A formulation employed in this invention may contain a pharmaceutical component as an active ingredient in addition to the compound (I) or its salt. As such pharmaceutically active component, for example, an anti-asthmatic agent (e.g., theophylline, procaterol, ketotifen, azelastine, seratrodast and the like), an anti-allergic agent (e.g., ketotifen, terfenadine, azelastine, epinastine and the like), an anti-inflammatory agent (e.g., dichlofenac sodium, ibuprofen, indomethacin and the like), an anti-bacterial agent (e.g., cefixime, cefdinir, ofloxacin, tosufloxacin and the like), an anti-fungal agent (e.g., fluconazole, itraconazole and the like), etc. are exemplified. These components are not to particularly be limited as long as an objective of the invention can be achieved, and may be added in a suitable amount. When the compound or its salt and a pharmaceutically active component described above are administered as active ingredients, two or more pharmaceutically active components may be formulated into a single formulation, or formulated independently and then administered simultaneously or at a certain interval. As specific examples of a dosage form, for example, tablet (including sugar-coated and film-coated tablets), pill, capsule (including microcapsule), granule, powder, dust, syrup, emulsion, suspension, formulation for injection, formulation for inhalation, ointment and the like are used. These formulations may be prepared by a standard method (e.g., one described in Japanese Pharmacopoeia).
While the amount of the compound (I) or its salt contained in an inventive formulation may vary depending on dosage forms, it ranges from about 0.01 to about 100% by weight based on the total weight of the formulation, preferably about 0.1 to about 50% by weight, more preferably about 0.5 to about 20% by weight.
Specifically a tablet is produced by mixing a pharmaceutical as it is with an excipient, a binder, a disintegrant or other suitable additives to form a uniform mixture which is then granulated by a suitable method and admixed with a glidant and the like and then compressed into a tablet, or by mixing a pharmaceutical as it is with an excipient, a binder, a disintegrant or other suitable additives to form a uniform mixture which is then directly compressed into a tablet, or by compressing a previously formulated granule directly, or after mixing uniformly with suitable additives, into a tablet. The formulation may contain a colorant and a flavor if necessary. The formulation may also be coated with a suitable coating.
A formulation for injection may be produced by dissolving, suspending or emulsifying a certain amount of a pharmaceutical in water for injection, physiological saline or Linger""s solution when preparing an aqueous formulation, or in an ordinary vegetable oil when preparing a non-aqueous formulation, whereby obtaining a certain volume, or by enclosing a certain amount of a pharmaceutical in a vial for injection.
As a carrier for an oral formulation, for example, a material used customarily in the art of drug formulation such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose and the like are used. As a carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion fluid and the like are used. Otherwise, additives employed customarily in the art of drug formulation may also be added appropriately.
The dose of the formulation may vary depending on age, body weight, condition, administration route, administration frequency and the like, and a daily dose as an active ingredient (the compound (I) or its salt) in an adult having asthma is usually about 0.1 to 100 mg/kg, preferably about 1 to 50 mg/kg, more preferably about 1 to 10 mg/kg, which is given orally once a day or twice as divided doses.
The present invention will be described in more detail hereinunder, with reference to Examples and Reference Examples. However, the present invention is not restricted by these examples, and changes and modifications can be made within the range which does not deviate the scope of the present invention.
Elution in the column chromatography in the following Reference Examples and Examples was conducted under observation by TLC (thin layer chromatography), unless otherwise specifically indicated. In the TLC observation, 60F254 produced by Merck Co. was used as the TLC plate, and the solvent employed in the column chromatography was used as the developing eluent. For the detection, a UV detector was used. As silica gel for the column chromatography, Silica Gel 60 (70-230 mesh) produced by Merck Co. was used. Room temperature as referred to hereinunder generally means temperatures falling between about 10xc2x0 C. and about 35xc2x0 C. For drying the extract solutions, sodium sulfate or magnesium sulfate was used.
The meanings of the abbreviations as used in the following Examples and Reference Examples are as follows:
NMR: Nuclear magnetic resonance spectrum
Hz: Herz
J: coupling constant
m: multiplet
q: quartet
t: triplet
d: doublet
s: singlet
b: broad
like: approximate